With the demonstration of glucagon's contributory role to the metabolic abnormalities of diabetes mellitus, it is now appropriate to determine if long-term glucagon suppression can provide any long-term benefit for the juvenile-type diabetic not otherwise available. Accordingly, the use of subcutaneous rather than intravenous somatostatin and somatostatin analogs will be tested in the setting of the Clinical Research Center of this institution to determine whether insulin plus subcutaneous doses of somatostatin or its analogs are as effective as insulin alone. In addition, orally administered somatostatin, which according to preliminary results is absorbed by humans, may also be tested. Finally, oligopeptides designed to saturate the circulating somatostatin binding protein but themselves devoid of intrinsic biologic activity will be tested to determine if their administration will augment the free fraction of somatostatin in the circulation by displacing endogenous somatostatin from its binding protein and thereby perhaps make possible inhibition of glucagon secretion by endogenous somatostatin. Finally, the role of "BPG", the "big plasma glucagon" which seems to be more prevalent in diabetic patients and which appears to contain biologically active glucagon, will be characterized. The pathogenesis of the syndrome of obesity-hyperglycemia and its possible relationship to inadequate somatostatin levels will be studied, in view of the demonstration in the ob/ob mouse that the hyperinsulinemic islets are low in somatostatin. The development of a technic for measuring circulating somatostatin in unextracted plasma has permitted the study of somatostatin physiology and pathophysiology. The results suggest that somatostatin secreted from the pancreas and stomach suppresses the rate at which ingested nutrients enter the circulation. If obese hyperglycemic individuals are deficient in somatostatin, this should be demonstrable by the appropriate provocative tests and might be correctable by replacement therapy, quite possibly replacement therapy by mouth. One of many projects in this category will be the testing of the foregoing hypothesis.